"Genotype-first" approaches on a curious case of idiopathic progressive cognitive decline.
"Genotype-first" approaches on a curious case of idiopathic progressive cognitive decline.
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“基因型优先”方法治疗特发性进行性认知衰退的奇怪病例
DOI：
10.1186/s12920-014-0066-9
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发表时间：
2014-12-03
影响因子：
2.7
通讯作者：
Wang K
中科院分区：
文献类型：
--
作者：
Shi L;Li B;Huang Y;Ling X;Liu T;Lyon GJ;Xu A;Wang K
在发展中国家，由于诊断经验有限，许多罕见神经系统疾病病例仍未得到诊断。我们在中国遇到了一个病例，两个兄弟姐妹都从6岁开始出现特发性进行性认知衰退，并被怀疑患有未确诊的神经系统疾病。初步临床评估包括病史审查、全面体格检查、代谢性疾病基因检测、血液检查和脑成像。我们使用Agilent SureSelect外显子捕获和Illumina HiSeq 2000平台进行外显子组测序，然后进行变异注释并选择符合隐性遗传模型的罕见共享突变。为了评估候选变体的功能影响，我们在血液和尿液中进行了广泛的生化测试，并通过蛋白质结构建模来研究它们可能的作用。外显子组测序鉴定NAGLU是最可能的具有复合杂合突变（在hg 19坐标中chr 17：40695717 C> T和chr 17：40693129 A> G）的候选基因，其被证明是致病性的。桑格测序证实了隐性遗传模式，导致圣菲利波综合征（粘多糖样变性IIIB）的遗传诊断。生化测试证实血液中α-N-乙酰氨基葡萄糖苷酶（由NAGLU编码）的活性完全丧失，以及尿液中硫酸皮肤素和硫酸乙酰肝素显著升高。结构建模揭示了这两种变体影响蛋白质结构稳定性的机制。成功诊断一种罕见的遗传性疾病与非典型表型表现证实，这种“基因型第一”的方法可以特别成功的世界上的地区，医学遗传学专业知识不足，成本高昂的深入表型。
In developing countries, many cases with rare neurological diseases remain undiagnosed due to limited diagnostic experience. We encountered a case in China where two siblings both began to develop idiopathic progressive cognitive decline starting from age six, and were suspected to have an undiagnosed neurological disease. Initial clinical assessments included review of medical history, comprehensive physical examination, genetic testing for metabolic diseases, blood tests and brain imaging. We performed exome sequencing with Agilent SureSelect exon capture and Illumina HiSeq2000 platform, followed by variant annotation and selection of rare, shared mutations that fit a recessive model of inheritance. To assess functional impacts of candidate variants, we performed extensive biochemical tests in blood and urine, and examined their possible roles by protein structure modeling. Exome sequencing identified NAGLU as the most likely candidate gene with compound heterozygous mutations (chr17:40695717C > T and chr17:40693129A > G in hg19 coordinate), which were documented to be pathogenic. Sanger sequencing confirmed the recessive patterns of inheritance, leading to a genetic diagnosis of Sanfilippo syndrome (mucopolysaccharidosis IIIB). Biochemical tests confirmed the complete loss of activity of alpha-N-acetylglucosaminidase (encoded by NAGLU) in blood, as well as significantly elevated dermatan sulfate and heparan sulfate in urine. Structure modeling revealed the mechanism on how the two variants affect protein structural stability. Successful diagnosis of a rare genetic disorder with an atypical phenotypic presentation confirmed that such “genotype-first” approaches can particularly succeed in areas of the world with insufficient medical genetics expertise and with cost-prohibitive in-depth phenotyping.
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影响因子：
120.7
作者：
Meikle, PJ;Hopwood, JJ;Carey, WF
通讯作者：
Carey, WF
影响因子：
9.8
作者：
Beetz, Christian;Pieber, Thomas R.;Auer-Grumbach, Michaela
通讯作者：
Auer-Grumbach, Michaela
影响因子：
64.8
作者：
Altshuler, David;Durbin, Richard M.;Abecasis, Goncalo R.;Bentley, David R.;Chakravarti, Aravinda;Clark, Andrew G.;Collins, Francis S.;De la Vega, Francisco M.;Donnelly, Peter;Egholm, Michael;Flicek, Paul;Gabriel, Stacey B.;Gibbs, Richard A.;Knoppers, Bartha M.;Lander, Eric S.;Lehrach, Hans;Mardis, Elaine R.;McVean, Gil A.;Nickerson, DebbieA.;Peltonen, Leena;Schafer, Alan J.;Sherry, Stephen T.;Wang, Jun;Wilson, Richard K.;Gibbs, Richard A.;Deiros, David;Metzker, Mike;Muzny, Donna;Reid, Jeff;Wheeler, David;Wang, Jun;Li, Jingxiang;Jian, Min;Li, Guoqing;Li, Ruiqiang;Liang, Huiqing;Tian, Geng;Wang, Bo;Wang, Jian;Wang, Wei;Yang, Huanming;Zhang, Xiuqing;Zheng, Huisong;Lander, Eric S.;Altshuler, David L.;Ambrogio, Lauren;Bloom, Toby;Cibulskis, Kristian;Fennell, Tim J.;Gabriel, Stacey B.;Jaffe, David B.;Shefler, Erica;Sougnez, Carrie L.;Bentley, David R.;Gormley, Niall;Humphray, Sean;Kingsbury, Zoya;Koko-Gonzales, Paula;Stone, Jennifer;McKernan, Kevin J.;Costa, Gina L.;Ichikawa, Jeffry K.;Lee, Clarence C.;Sudbrak, Ralf;Lehrach, Hans;Borodina, Tatiana A.;Dahl, Andreas;Davydov, Alexey N.;Marquardt, Peter;Mertes, Florian;Nietfeld, Wilfiried;Rosenstiel, Philip;Schreiber, Stefan;Soldatov, Aleksey V.;Timmermann, Bernd;Tolzmann, Marius;Egholm, Michael;Affourtit, Jason;Ashworth, Dana;Attiya, Said;Bachorski, Melissa;Buglione, Eli;Burke, Adam;Caprio, Amanda;Celone, Christopher;Clark, Shauna;Conners, David;Desany, Brian;Gu, Lisa;Guccione, Lorri;Kao, Kalvin;Kebbel, Andrew;Knowlton, Jennifer;Labrecque, Matthew;McDade, Louise;Mealmaker, Craig;Minderman, Melissa;Nawrocki, Anne;Niazi, Faheem;Pareja, Kristen;Ramenani, Ravi;Riches, David;Song, Wanmin;Turcotte, Cynthia;Wang, Shally;Mardis, Elaine R.;Dooling, David;Fulton, Lucinda;Fulton, Robert;Weinstock, George;Durbin, Richard M.;Burton, John;Carter, David M.;Churcher, Carol;Coffey, Alison;Cox, Anthony;Palotie, Aarno;Quail, Michael;Skelly, Tom;Stalker, James;Swerdlow, Harold P.;Turner, Daniel;De Witte, Anniek;Giles, Shane;Gibbs, Richard A.;Wheeler, David;Bainbridge, Matthew;Challis, Danny;Sabo, Aniko;Yu, Fuli;Yu, Jin;Wang, Jun;Fang, Xiaodong;Guo, Xiaosen;Li, Ruiqiang;Li, Yingrui;Luo, Ruibang;Tai, Shuaishuai;Wu, Honglong;Zheng, Hancheng;Zheng, Xiaole;Zhou, Yan;Yang, Huanming;Marth, Gabor T.;Garrison, Erik P.;Huang, Weichun;Indap, Amit;Kural, Deniz;Lee, Wan-Ping;Leong, Wen Fung;Huang, Weichun;Indap, Amit;Kural, Deniz;Lee, Wan-Ping;Leong, Wen Fung;Quinlan, Aaron R.;Stewart, Chip;Stromberg, Michael P.;Ward, Alistair N.;Wu, Jiantao;Lee, Charles;Mills, Ryan E.;Shi, Xinghua;Daly, Mark J.;DePristo, Mark A.;Altshuler, David L.;Ball, Aaron D.;Banks, Eric;Bloom, Toby;Browning, Brian L.;Cibulskis, Kristian;Fennell, Tim J.;Garimella, Kiran V.;Grossman, Sharon R.;Handsaker, Robert E.;Hanna, Matt;Hartl, Chris;Jaffe, David B.;Kernytsky, Andrew M.;Korn, Joshua M.;Li, Heng;Maguire, Jared R.;McCarroll, Steven A.;McKenna, Aaron;Nemesh, James C.;Philippakis, Anthony A.;Poplin, Ryan E.;Price, Alkes;Rivas, Manuel A.;Sabeti, Pardis C.;Schaffner, Stephen F.;Shefler, Erica;Shlyakhter, Ilya A.;Cooper, David N.;Ball, Edward V.;Mort, Matthew;Phillips, Andrew D.;Stenson, Peter D.;Sebat, Jonathan;Makarov, Vladimir;Ye, Kenny;Yoon, Seungtai C.;Bustamante, Carlos D.;Clark, Andrew G.;Boyko, Adam;Degenhardt, Jeremiah;Gravel, Simon;Gutenkunst, Ryan N.;Kaganovich, Mark;Keinan, Alon;Lacroute, Phil;Ma, Xia;Reynolds, Andy;Clarke, Laura;Flicek, Paul;Cunningham, Fiona;Herrero, Javier;Keenen, Stephen;Kulesha, Eugene;Leinonen, Rasko;McLaren, WilliamM.;Radhakrishnan, Rajesh;Smith, Richard E.;Zalunin, Vadim;Zheng-Bradley, Xiangqun;Korbel, Jan O.;Stuetz, Adrian M.;Humphray, Sean;Bauer, Markus;Cheetham, R. Keira;Cox, Tony;Eberle, Michael;James, Terena;Kahn, Scott;Murray, Lisa;Ye, Kai;De La Vega, Francisco M.;Fu, Yutao;Hyland, Fiona C. L.;Manning, Jonathan M.;McLaughlin, Stephen F.;Peckham, Heather E.;Sakarya, Onur;Sun, Yongming A.;Tsung, Eric F.;Batzer, Mark A.;Konkel, Miriam K.;Walker, Jerilyn A.;Sudbrak, Ralf;Albrecht, Marcus W.;Amstislavskiy, Vyacheslav S.;Herwig, Ralf;Parkhomchuk, Dimitri V.;Sherry, Stephen T.;Agarwala, Richa;Khouri, Hodam.;Morgulis, Aleksandr O.;Paschall, Justin E.;Phan, Lon D.;Rotmistrovsky, Kirill E.;Sanders, Robert D.;Shumway, Martin F.;Xiao, Chunlin;McVean, Gil A.;Auton, Adam;Iqbal, Zamin;Lunter, Gerton;Marchini, Jonathan L.;Moutsianas, Loukas;Myers, Simon;Tumian, Afidalina;Desany, Brian;Knight, James;Winer, Roger;Craig, David W.;Beckstrom-Sternberg, Steve M.;Christoforides, Alexis;Kurdoglu, Ahmet A.;Pearson, Johnv.;Sinari, Shripad A.;Tembe, Waibhav D.;Haussler, David;Hinrichs, Angie S.;Katzman, Sol J.;Kern, Andrew;Kuhn, Robert M.;Przeworski, Molly;Hernandez, Ryan D.;Howie, Bryan;Kelley, Joanna L.;Melton, S. Cord;Abecasis, Goncalo R.;Li, Yun;Anderson, Paul;Blackwell, Tom;Chen, Wei;Cookson, William O.;Ding, Jun;Kang, Hyun Min;Lathrop, Mark;Liang, Liming;Moffatt, Miriam F.;Scheet, Paul;Sidore, Carlo;Snyder, Matthew;Zhan, Xiaowei;Zoellner, Sebastian;Awadalla, Philip;Casals, Ferran;Idaghdour, Youssef;Keebler, John;Stone, Eric A.;Zilversmit, Martine;Jorde, Lynn;Xing, Jinchuan;Eichler, Evan E.;Aksay, Gozde;Alkan, Can;Hajirasouliha, Iman;Hormozdiari, Fereydoun;Kidd, Jeffrey M.;Sahinalp, S. Cenk;Sudmant, Peter H.;Mardis, Elaine R.;Chen, Ken;Chinwalla, Asif;Ding, Li;Koboldt, Daniel C.;McLellan, Mike D.;Dooling, David;Weinstock, George;Wallis, John W.;Wendl, Michael C.;Zhang, Qunyuan;Durbin, Richard M.;Albers, Cornelis A.;Ayub, Qasim;Balasubramaniam, Senduran;Barrett, Jeffrey C.;Carter, David M.;Chen, Yuan;Conrad, Donald F.;Danecek, Petr;Dermitzakis, Emmanouil T.;Hu, Min;Huang, Ni;Hurles, Matt E.;Jin, Hanjun;Jostins, Luke;Keane, Thomas M.;Keane, Thomas M.;Le, Si Quang;Lindsay, Sarah;Long, Quan;MacArthur, Daniel G.;Montgomery, Stephen B.;Parts, Leopold;Stalker, James;Tyler-Smith, Chris;Walter, Klaudia;Zhang, Yujun;Gerstein, Mark B.;Snyder, Michael;Abyzov, Alexej;Abyzov, Alexej;Balasubramanian, Suganthi;Bjornson, Robert;Du, Jiang;Grubert, Fabian;Habegger, Lukas;Haraksingh, Rajini;Jee, Justin;Khurana, Ekta;Lam, Hugo Y. K.;Leng, Jing;Mu, Xinmeng Jasmine;Urban, Alexander E.;Zhang, Zhengdong;Li, Yingrui;Luo, Ruibang;Marth, Gabor T.;Garrison, Erik P.;Kural, Deniz;Quinlan, Aaron R.;Stewart, Chip;Stromberg, Michael P.;Ward, Alistair N.;Wu, Jiantao;Lee, Charles;Mills, Ryan E.;Shi, Xinghua;McCarroll, Steven A.;Banks, Eric;DePristo, Mark A.;Handsaker, Robert E.;Hartl, Chris;Korn, Joshua M.;Li, Heng;Nemesh, James C.;Sebat, Jonathan;Makarov, Vladimir;Ye, Kenny;Yoon, Seungtai C.;Degenhardt, Jeremiah;Kaganovich, Mark;Clarke, Laura;Smith, Richard E.;Zheng-Bradley, Xiangqun;Korbel, Jan O.;Humphray, Sean;Cheetham, R. Keira;Eberle, Michael;Kahn, Scott;Murray, Lisa;Ye, Kai;De la Vega, Francisco M.;Fu, Yutao;Peckham, Heather E.;Sun, Yongming A.;Batzer, Mark A.;Konkel, Miriam K.;Xiao, Chunlin;Iqbal, Zamin;Desany, Brian;Blackwell, Tom;Snyder, Matthew;Xing, Jinchuan;Eichler, Evan E.;Aksay, Gozde;Alkan, Can;Hajirasouliha, Iman;Hormozdiari, Fereydoun;Kidd, Jeffrey M.;Chen, Ken;Chinwalla, Asif;Ding, Li;McLellan, Mike D.;Wallis, John W.;Hurles, Matt E.;Conrad, Donald F.;Walter, Klaudia;Zhang, Yujun;Gerstein, Mark B.;Snyder, Michael;Abyzov, Alexej;Du, Jiang;Grubert, Fabian;Haraksingh, Rajini;Jee, Justin;Khurana, Ekta;Lam, Hugo Y. K.;Leng, Jing;Mu, Xinmeng Jasmine;Urban, Alexander E.;Zhang, Zhengdong;Gibbs, Richard A.;Bainbridge, Matthew;Challis, Danny;Coafra, Cristian;Dinh, Huyen;Kovar, Christie;Lee, Sandy;Muzny, Donna;Nazareth, Lynne;Reid, Jeff;Sabo, Aniko;Yu, Fuli;Yu, Jin;Marth, Gabor T.;Garrison, Erik P.;Indap, Amit;Leong, Wen Fung;Quinlan, Aaron R.;Stewart, Chip;Ward, Alistair N.;Wu, Jiantao;Cibulskis, Kristian;Fennell, Tim J.;Gabriel, Stacey B.;Garimella, Kiran V.;Hartl, Chris;Shefler, Erica;Sougnez, Carrie L.;Wilkinson, Jane;Clark, Andrew G.;Gravel, Simon;Grubert, Fabian;Clarke, Laura;Flicek, Paul;Smith, Richard E.;Zheng-Bradley, Xiangqun;Sherry, Stephen T.;Khouri, Hoda M.;Paschall, Justin E.;Shumway, Martin F.;Xiao, Chunlin;McVean, Gil A.;Katzman, Sol J.;Abecasis, Goncalo R.;Blackwell, Tom;Mardis, Elaine R.;Dooling, David;Fulton, Lucinda;Fulton, Robert;Koboldt, Daniel C.;Durbin, Richard M.;Balasubramaniam, Senduran;Coffey, Allison;Keane, Thomas M.;MacArthur, Daniel G.;Palotie, Aarno;Scott, Carol;Stalker, James;Tyler-Smith, Chris;Gerstein, Mark B.;Balasubramanian, Suganthi;Chakravarti, Aravinda;Knoppers, Bartha M.;Peltonen, Leena;Abecasis, Goncalo R.;Bustamante, Carlos D.;Gharani, Neda;Gibbs, Richard A.;Jorde, Lynn;Kaye, Jane S.;Kent, Alastair;Li, Taosha;McGuire, Amy L.;McVean, Gil A.;Ossorio, Pilar N.;Rotimi, Charles N.;Su, Yeyang;Toji, Lorraine H.;Tyler-Smith, Chris;Brooks, Lisa D.;Felsenfeld, Adam L.;McEwen, Jean E.;Abdallah, Assya;Juenger, Christopher R.;Clemm, Nicholas C.;Collins, Francis S.;Duncanson, Audrey;Green, Eric D.;Guyer, Mark S.;Peterson, Jane L.;Schafer, Alan J.;Abecasis, Goncalo R.;Altshuler, David L.;Auton, Adam;Brooks, Lisa D.;Durbin, Richard M.;Gibbs, Richard A.;Hurles, Matt E.;McVean, Gil A.
通讯作者：
McVean, Gil A.
DOI：
10.1093/bioinformatics/btp352
发表时间：
2009-08-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Li H;Handsaker B;Wysoker A;Fennell T;Ruan J;Homer N;Marth G;Abecasis G;Durbin R;1000 Genome Project Data Processing Subgroup
通讯作者：
1000 Genome Project Data Processing Subgroup
影响因子：
12.3
作者：
Gilissen C;Hoischen A;Brunner HG;Veltman JA
通讯作者：
Veltman JA